Phenothiazines having antihypertensive effect



United States Patent 3,239,517 PHENOTHIAZINES HAVING ANTIHYIER- TENSIVE EFFECT Lajos Toldy, 53 Villanyi ut., and Jozsef Borsi, 90 Bartok Bela ut., both of Budapest XI, Hungary, and Marton Fekete, 49 F0 utca, Budapest II, Hungary N0 Drawing. Filed Oct. 12, 1964, Ser. No. 403,377 1 Claim. (Cl. 260-243) The present application is a continuation-in-part of application Serial No. 232,324, filed October 5, 1962, now abandoned.

This invention relates to new phcnothiazine derivatives having the general formula k.) (I) and therapeutically acceptable salts thereof, in which A is selected from the class consisting of hydrogen, chlorine and methoxy, and Z is a bivalent carbon chain having 2 to 7 carbon atoms.

The new phenothiazine derivatives having the general Formula I, as contrasted with the hitherto known phenothiazine derivatives, have almost no sedative or tranquilizing effect but rather show a strong hypotensive effect.

Thus, for example, 3-chloro-IO-gam-ma-hepta-methyleneimino-propyl-phenothiazine causes hypotension for several hours on Waking and sleeping animals in doses ranging from 0.1 to 0.5 mg./kg. of body weight. During the duration of the hypotensive effect, the hypertension caused by chemical agents such as adrenaline, nor-adrenaline, or vasopressine, or by pressing the carotid on both sides as well as by stimulating electrically the vasopressor zones of the hypothalmus, is strongly inhibited. By such investigations it has been established that in the case of the phenothiazine derivatives having the general Formula I, the sedative and the hypotensive effects can be separated, and the hypotensive effects can be produced without corresponding sedative or tranquilizing effects. Morevover, it has been established that in the case of prolonged treatment no increase in dosage is required by virtue of habituation.

These new compounds are advantageously used for therapeutic purposes in the form of their salts formed with nontoxic acids. Among such acids are maleic, fumaric, bezoic, ascorbic, succinic, bis-methylene-salicylic, methane-sulfonic, ethane-sulfonic, acetic, propionic, tartaric, salicylic, citric, theophy-lline-acetic, hydrochloric and phosphoric.

Several methods for producing compounds having the general Formula I are as follows:

(1) A heterocyclic compound having the formula i H (II) is condensed with a compound selected from the class consisting of amines and their salts. In the above formula, A is selected from the class consisting of hydrogen, chlorine and methoxy. Among the amines, those represented by the formula (III) and its salts may be used, where Z is as above and Y is a reactive ester residue such as a halogen atom, a sulfuric-acid ester, or an aliphatic or aromatic sulfonicacid ester residue.

(2) A heterocylic compound having the formula Z-Y (IV) in which A, Z and Y have the above meanings, is condensed with an amine having the formula HNK (\CH2)1 \J (3) A heterocyclic compound having the formula do-o-z-KTcH:

is heated at a temperature exceeding C. A and Z have the above meaning-s.

The products of the processes described above can be transformed to salts by treating with a mineral or organic acid, or they can be quaternized in a way known per se, as by treating with an alkyl halide or alkyl sulfonate.

Quaternary derivatives of the new compounds having the general Formula I can also be prepared by reacting a heterocyclic compound of Formula IV with an amine having the formula RN (CH2)7 kJ (VII) in which R is selected from the class consisting of alkyl, aralkyl, and substituted aralkyl groups.

Reaction 1 described above can be carried out in a solvent or not, and with or without a condensing agent. As solvents, aromatic hydrocarbons such as toluene or xylene, esters such as ethyl acetate, or tertiary amides such as dimethyl formamide can be used. If a condensing agent is employed, as is preferable, alkali metals can be used, or there may be used alkali-metal derivatives such as hydrides, amides, hydroxides, alcoholates, or alkyl or aryl derivatives. Among the desirable condensing agents are metallic sodium or potassium, sodium amide, finely divided sodium or potassium hydroxide, lithium or sodium hydride, sodium tertiary butylate, butyl lithium, phenyl lithium or phenyl sodium. It is preferable to carry out the condensation reaction at the boiling temperature of the solvent.

Reaction 2 can be carried out either at room temperature or at elevated temperature. The condensation can be carried out in the presence of an inert solvent such as an aromatic hydrocarbon or an alcohol or the like. Acid-binding agents can also be used, if desired; and the excess of the amine having the general Formula V can also be used as the acid-binding agent.

Reaction 3 is preferably carried out at temperatures between to 200 C. Heating should be continued until the evolution of carbon dioxide ceases. This process can be carried out without a solvent or in an inert diluent such as biphenyl, diphenyl oxide, chlorinated aromatic hydrocarbons, or a standard diluent for decarboxylating reactions, such as quinoline or other weak organic bases.

To enable those skilled in the art to practice this invention, the following illustrative examples are given:

Example 1 26 g. of 3-chlorophenothiazine (Beilsteins nomenclature) are boiled for 2 hours with 7 g. of sodium amide in 200 ml. of absolute xylene.

solution of 26 g. of N-(3-chloropropyl)-heptamethyleneimine in 50 ml. of absolute xylene is added dropwise.

After boiling for 2 hours, the cooled mixture is vacuum filtered, washed with 200 ml. of water, and then agitated with 300 ml. of 2 N hydrochloric acid. At this time the hydrochloric acid salt of 3-chloro-1'0 (3' -heptamethyleneimino)-propylphenothiazine, whichh'as low solubility in water, is precipitated. The aqueous portion is separated from the decanted liquid mixture, and after the above precipitation it is rendered basic with a N sodiumhydroxide solution. The free base is extracted with benzene and distilled off. Boiling point: 250255 C. at 0.5 mm. Hg. Yield: 26 g. of 3-chloro-10-(3'-heptamethyleneimino)-propyl-phenothiazine. The ethane sul fonate precipitated from the methyl-ketonic solution of the product melts at 150-152 C. The N-(3-chloropropyl)-heptamethyleneimine used as starting material is prepared by reacting 1-chloro-3-bromo-tropeine with heptamethyleneimine.

Boiling point at 0.4 mm. Hg, 82-84 C.

Example 2 Then, with further boiling and mixing, over a period of one and one-half hours, a-

during 1 hour the. solution in 50 ml. of absolutexylene of. 10 g. of N-(2-chloroethy1)-heptamethyleneirnine is added dropwise. After postboiling-for 1 hour, the cooledmixture is vacuum filtered,v agitated. with water twotirnes.

and extracted with 200 ml. of a aqueous tartaric-, acid solution. Boiling point: 245-250" C. at 0.6 mm. Hg. Yield:, 13 g. of 10-(2-heptamethyleneimino) -ethyl-pheno thiazine. The; ethane sulfona-te of the product melts at 124-125 C.

The N-( 2-chloroethyl)-heptamethyleneimine .,used as starting. material is prepared by synthesizing N-(2-oxy1 ethyl)-heptamethyleneimine- (boiling point: 100-105 C.:.

. at 5 mm. Hg) by reacting,heptamethyleneimine with 1 8 g. of 3-c'h1oro-10-(3-mesyloxy)-propyl-phenothia- V zine (L. Toldy, I. Fabricius, Chem. and Ind., 1957, 665) are shaken in 300 ml. of absolute alcohol with 12 g. of heptamethyleneimine until dissolution, thenthe solution is left to stand for a week, thereafter the alcohol is distilled off and the residue taken up with chloroform. The chloroformous solution is shaken out at first with a 5 N sodium-hydroxide solution, then the 3-chloro-l0-(3'- heptamethyleneimino)-propyl-phenothiazine is extracted with the method described in Example 1, and also further on the method described in Example 1 is followed. After precipitation from an alcoholous solution, the fumarate of the obtained 3-chloro-10-(3'-heptamethyleneimino)- propyl-phenothiazine melts at 140-150 C.

Example 3 15 g. of phenothiazine are boiled for 1 hour with 4.5

g. of sodium amide in 150 m1. of xylene, then with further boiling and stirring, the solution of 18 g. of N-(3- chloropropyl)-heptamethyleneimine in 50 ml. of absolute xylene is added dropwise. After boiling for 2 hours, the cooled mixture is vacuum filtered, agitated with Water two times and extracted with 250 ml. of 15% tartaric acid solution. The separated aqueous phase is rendered basic with a 10 N sodium hydroxide solution, the separated-out oil is absorbed with benzene, and after distilling oil the benzene, the oil is distilled 01f.

Boiling point at 0.4 mm. Hg, 235 C. Yield: 20 g.

The ethane sulfonate precipitated in methylethylketone from the product 10(3T-heptamethyleneimino)propylphenothiazine melts at 140-142" C.

Example 5 10 g. of phenothiazine are boiled with 3 g. of sodium amide for half an hour in 100 ml. absolute xylene, then stirring, 22 .g. of N-(3-chloro-propyl -heptamethylener,

ethyleneoxide and this product 'ischlorinated with thionyl chloride, thereby obtaining the desired 'produetthe chloro- I.

hydrate of which melts a-t'196197 C."

Example 6 i 7.3 g. of 10 (2 J- tosyloxy), propyl-i phenothiazine are boiled for 8 hours with 9 g. of heptamethyleneimine in 100 ml. of absolute xylene. Thereafter the cooled mixture is agitated with water two times, then'extracted ,with a 15% aqueous tartaric-acid solution. Theoil separating out from the boiled aqueou-s phase is taken up with ben zene and it is distilled'ofli.

The. ethane sulfonate of the product 10-(2'-hepta-I methyleneimino).- propyl phenothiazine melts at. 143

Example 71 22.3 g. of 3-methoxy-phenothiazinei are boiled for one and a half hours with 4.8 g. of sodium amide in 200 ml. of absolute xylene- Then while further boiling and imine dissolved in 50 ml. of absolute xylenev are added dropwise during one hour. After postboiling for one hour the cooled mixture is vacuum filtered, washed. twice with water and extracted with 200 mm. of a 15% aqueous, The aqueous phase ;is renderedtartaric-acid solution. basic with a 10 N s0dium-hydroxide solution and the separated oil is. absorbed with benzene.

methoxy 1O (3-heptamethyleneimino)-propyl-phenor thiazine isiobtained. Boiling point: 250-260 C. at 0.4 mm. Hg.,

In the above examples, in which the N (2-chloroethyl)- heptamethyleneimine and N (3 chloropropyl)'- heptamethyleneiminez .is added, corresponding; results are obtainedby utilizing instead the homologous halo'alkylheptamethyleneimines comprising the butyl, isobutyl, ;pentyl, hexyl, isopentyl, isohexyl, hepta and isohepta compounds.

The tranqualizing or sedative elfects of- 3-chloro-l0- (gamma heptamethyleneimino-propyl) phenothiazine fumarate (herein-after called hepta.) were compared with 3 chloro-10-(gamma-hexamethyleneiminorpropyl)f4 phenothiazine furnarate (hereinafter; called hexa), on mice, by the aid of the method of P. B.' Dews (British J. Pharmacol. 8, 46/153), taking .into accounta modifica- I tion elaborated by the inventors (Borsy et al., Arch. Int.

Chloropromazine 1.5 Hexa 1.7 Hept'a 7.0

Pharmacodyn; 124, 1960).. The results are reported below.

The hexa compound had a base content of 76% while the hepta compound had-a base content of 78%. The

50% orientation reflex-inhibiting dosages, as compared with that of chloropromazine as a standard, are given in the table below, in units of an effective dose of 50 mm./ kg. of body weight, administered intraperitoneally.

From the above table, it will be'recognized that the hexa compound and chloropromazine are about on the-- same level with regard ,to producing tranquilizing or sedat ve effects, but that the .hepta compound is four or five tunes weaker :in this regard than either chloropro;

After distilling off the benzene. the oil is distilled off. A product of 3- and therapeutically acceptable salts thereof, wherein A is selected from the class consisting of hydrogen, chlorine and methoxy.

References Cited by the Examiner UNITED STATES PATENTS 10/1961 Mull 260239 FOREIGN PATENTS 813,861 5/1959 Great Britain. 828,495 2/1960 Great Britain. 831,091 3/ 1960 Great Britain. 845,943 8/ 1960 Great Britain.

OTHER REFERENCES Chemical Abstracts, volume 59, column 2809 (1963) (abstract of Pai et -al., Hau Hseuh Hsueh Pao, volume 29, pages 28-36) (1963).

Craig et al.: J. Org. Chem., volume 26, pages 138 (January 1961) Hollister: Ann. of Internal Medicine, volume 51, page 1041 (1959).

Villani et al.: J. Med. and Pharm. Chem., volume 5, pages 373-374 (March 1962).

\VALTER A. MODANCE, Primary Examiner.

JOHN D. RANDOLPH, Examiner. 

